Population-Level Benefits from Providing Effective HIV Prevention Means to Pregnant Women in High Prevalence Settings

Background:HIV prevalence among pregnant women in Southern Africa is extremely high. Epidemiological studies suggest that pregnancy increases the risk of HIV sexual acquisition and that HIV infections acquired during pregnancy carry higher risk of mother-to-child transmission (MTCT). We analyze the potential benefits from extending the availability of effective microbicide to pregnant women (in addition to non-pregnant women) in a wide-scale intervention.Methods and Findings:A transmission dynamic model was designed to assess the impact of microbicide use in high HIV prevalence settings and to estimate proportions of new HIV infections, infections acquired during pregnancy, and MTCT prevented over 10 years. Our analysis suggests that consistent use of microbicide with 70% efficacy by 60% of non-pregnant women may prevent approximately 40% and 15% of new infections in women and men respectively over 10 years, assuming no additional increase in HIV risk to either partner during pregnancy (RRHIV/preg = 1). It may also prevent 8-15% MTCT depending on the increase in MTCT risk when HIV is acquired during pregnancy compared to before pregnancy (RRMTCT/preg). Extending the microbicides use during pregnancy may improve the effectiveness of the intervention by 10% (RRHIV/preg = 1) to 25% (RRHIV/preg = 2) and reduce the number of HIV infections acquired during pregnancy by 40% to 70% in different scenarios. It may add between 6% (RRHIV/preg = 1, RRMTCT/preg = 1) and 25% (RRHIV/preg = 2, RRMTCT/preg = 4) to the reduction in the residual MTCT.Conclusion:Providing safe and effective microbicide to pregnant women in the context of wide-scale interventions would be desirable as it would increase the effectiveness of the intervention and significantly reduce the number of HIV infections acquired during pregnancy. The projected benefits from covering pregnant women by the HIV prevention programs is more substantial in communities in which the sexual risk during pregnancy is elevated. © 2013 Dimitrov et al

Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

<p>Abstract</p> <p>Background</p> <p>To date different vaginal gel microbicides have been evaluated in phase 2b/3 trials, but none have demonstrated effectiveness for preventing HIV infection. Failure to demonstrate effectiveness however does not necessarily indicate that a product is truly inefficacious, as several sources of efficacy dilution may compromise our ability to identify products that may have been truly efficacious.</p> <p>Methods</p> <p>For four individual sources of dilution, we describe the dilution mechanisms and quantify the expected effectiveness. An overall expected effectiveness that combines all sources of dilution in a trial is derived as well.</p> <p>Results</p> <p>Under conditions that have been observed in recent microbicide trials, the overall expected effectiveness assuming an active gel with true efficacy of 50% and 75% are in the range of [16%; 33%] and [28%; 50%], respectively, when considering the four major sources of dilution. In contrast the diluting effect due to adherence alone (assuming an adherence of 80%) leads to higher expected effectiveness, 40% and 60% assuming an active gel with true efficacy of 50% and 75%, respectively. Individual sources of dilution may demonstrate a small effect when evaluated independently, but the overall dilution effect in a trial with several sources of dilution can be quite substantial.</p> <p>Conclusion</p> <p>Currently planned phase 2b/3 microbicide trials of new candidate vaginal microbicides are not immune from these shortcomings. A good understanding of dilution effects is necessary to properly interpret microbicide trial results and to identify products worthy of further development and evaluation. Greater attention should be devoted to reducing and assessing the impact of efficacy dilution and to carefully selecting the effect size in the design of future trials.</p

Surviving infant mortality in the hierarchical merging scenario

We examine the effects of gas expulsion on initially sub-structured and out-of-equilibrium star clusters. We perform $N$-body simulations of the evolution of star clusters in a static background potential before removing that potential to model gas expulsion. We find that the initial star formation efficiency is not a good measure of the survivability of star clusters. This is because the stellar distribution can change significantly, causing a large change in the relative importance of the stellar and gas potentials. We find that the initial stellar distribution and velocity dispersion are far more important parameters than the initial star formation efficiency, and that clusters with very low star formation efficiencies can survive gas expulsion. We suggest that it is variations in cluster initial conditions rather than in their star formation efficiencies that cause some clusters to be destroyed while a few survive.Comment: 9 pages, 10 figures, 1 tabl

The M/L ratio of massive young clusters

We point out a strong time-evolution of the mass-to-light conversion factor \eta commonly used to estimate masses of dense star clusters from observed cluster radii and stellar velocity dispersions. We use a gas-dynamical model coupled with the Cambridge stellar evolution tracks to compute line-of-sight velocity dispersions and half-light radii weighted by the luminosity. Stars at birth are assumed to follow the Salpeter mass function in the range [0.15--17 M_\sun]. We find that $\eta$, and hence the estimated cluster mass, increases by factors as large as 3 over time-scales of 20 million years. Increasing the upper mass limit to 50 M_\sun leads to a sharp rise of similar amplitude but in as little as 10 million years. Fitting truncated isothermal (Michie-King) models to the projected light profile leads to over-estimates of the concentration par ameter c of $\delta c\approx 0.3$ compared to the same functional fit applied to the proj ected mass density.Comment: Draft version of an ApJ lette

HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention

The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections

HIV testing and engagement with the HIV treatment cascade among men who have sex with men in Africa: A systematic review and meta-analysis

Background HIV disproportionately affects gay, bisexual, and other men who have sex with men (MSM) in Africa, where many countries criminalise same-sex behaviour. We assessed changes in the engagement of African MSM with HIV testing and treatment cascade stages over time, and the influence of anti-LGBT legislation and stigma. Methods We systematically searched the peer-reviewed literature to October 10th , 2018 for studies and extracted or derived estimates of HIV testing and/or engagement with the HIV treatment cascade among African MSM from published reports. We derived pooled estimates using inverse-variance random-effects models. We used subgroup and meta-regression analysis to assess associations between testing and status awareness outcomes and study and participant characteristics including the severity of country-level anti-LGBT legislation. Findings Our searches identified 75 independent eligible studies that provided estimates for 44,993 MSM across one or more of five testing and treatment cascade outcomes. HIV testing increased significantly over time overall, with pooled overall proportions of MSM ever tested of 67·3% (95%Confidence interval 62·1-72·3%,N=44) and tested in the past 12 months of 50·1% (42·4-57·8%,N=31) post-2011 – 14% and 18% points higher than pre-2011, respectively. Post-2011, ever testing was highest in Southern(80·0%) and lowest in Northern(34·4%) and Central(56·1%) Africa, with the greatest increase in Western Africa(from 42·4 to 70·9%). Levels of both testing outcomes and status awareness were statistically significantly lower in countries with the most severe anti-LGBT legislation. Few estimates were available for later stages of the treatment cascade. Available data post61 2011 suggest that the pooled proportion of MSM HIV-positive aware has remained low (18·5%, 12·5-25·3%,N=28) whereas proportions of current ART use were 23·7% (15·5- 33·0%,N=14) among all MSM living with HIV and 53·4% (36·9-69·5%,N=6) among MSM HIV-positive aware. Levels of viral suppression among MSM currently on ART were good (pooled: 75·6%, 64·4-85·5%,N=4), but low among all MSM living with HIV (pooled: 24·7%, 18·8-31·2%,N=4). Interpretation Available data suggests that levels of HIV status awareness among MSM living with HIV in Africa remain low, despite recent improvements in HIV testing; limited data is available on levels of engagement in care, ART use and viral suppression. We found that severe anti LGBT legislation was associated with lower HIV testing and status awareness. Achieving UNAIDS 90-90-90 targets will require substantial improvements

Global Nonradial Instabilities of Dynamically Collapsing Gas Spheres

Self-similar solutions provide good descriptions for the gravitational collapse of spherical clouds or stars when the gas obeys a polytropic equation of state, $p=K\rho^\gamma$ (with $\gamma\le 4/3$). We study the behaviors of nonradial perturbations in the similarity solutions of Larson, Penston and Yahil, which describe the evolution of the collapsing cloud prior to core formation. Our global stability analysis reveals the existence of unstable bar-modes ($l=2$) when $\gamma\le 1.09$. In particular, for the collapse of isothermal spheres, which applies to the early stages of star formation, the $l=2$ density perturbation relative to the background, $\delta\rho({\bf r},t)/\rho(r,t)$, increases as $(t_0-t)^{-0.352}\propto \rho_c(t)^{0.176}$, where $t_0$ denotes the epoch of core formation, and $\rho_c(t)$ is the cloud central density. Thus, the isothermal cloud tends to evolve into an ellipsoidal shape (prolate bar or oblate disk, depending on initial conditions) as the collapse proceeds. In the context of Type II supernovae, core collapse is described by the $\gamma\simeq 1.3$ equation of state, and our analysis indicates that there is no growing mode (with density perturbation) in the collapsing core before the proto-neutron star forms, although nonradial perturbations can grow during the subsequent accretion of the outer core and envelope onto the neutron star. We also carry out a global stability analysis for the self-similar expansion-wave solution found by Shu, which describes the post-collapse accretion (``inside-out'' collapse) of isothermal gas onto a protostar. We show that this solution is unstable to perturbations of all $l$'s, although the growth rates are unknown.Comment: 28 pages including 7 ps figures; Minor changes in the discussion; To be published in ApJ (V.540, Sept.10, 2000 issue

Impact of High-Risk Sex and Focused Interventions in Heterosexual HIV Epidemics: A Systematic Review of Mathematical Models

Background: The core-group theory of sexually transmitted infections suggests that targeting prevention to high-risk groups (HRG) could be very effective. We aimed to quantify the contribution of heterosexual HRGs and the potential impact of focused interventions to HIV transmission in the wider community. Methods: We systematically identified studies published between 1980 and 2011. Studies were included if they used dynamical models of heterosexual HIV transmission, incorporated behavioural heterogeneity in risk, and provided at least one of the following primary estimates in the wider community (a) the population attributable fraction (PAF) of HIV infections due to HRGs, or (b) the number per capita or fraction of HIV infections averted, or change in HIV prevalence/incidence due to focused interventions. Findings: Of 267 selected articles, 22 were included. Four studies measured the PAF, and 20 studies measured intervention impact across 265 scenarios. In low-prevalence epidemics (≤5% HIV prevalen